Hypoxic tumor cell radiosensitizers are compounds that selectively increase the sensitivity of hypoxic cells in tumors to radiation. Various heterocyclic compounds, in particular, those with oxidized nitrogen moieties have been used for this purpose. Indeed, it has been postulated that the oxidized nitrogen functionality is responsible for this activity. Nitroimidazoles, particularly misonidazole (MIS) and metronidazole have been studied extensively, and MIS is commonly used as a standard in in vitro and in vivo tests for radiosensitizing activity. (See, e.g., Asquith, et al, Radiation Res (1974) 60:108-118; Hall, et al, Brit J Cancer (1978) 37:567-569; Brown, et al, Radiation Res (1980) 82:171-190; and U.S. Pat. No. 4,371,540. U.S. Ser. No. 439,435, filed Nov. 5, 1982 describes certain 1-substituted 3(5)-nitro-s-triazoles as hypoxic tumor cell radiosensitizers; U.S. Ser. Nos. 556,308 and 556,311, both filed Nov. 30, 1983 disclose similar radiosensitizing activity of quinoxaline-1,4-dioxide derivatives.
The present invention provides a new group of radiosensitizers that do not contain oxidized nitrogen--the substituted benzamides and their thio analogs. Some members of this group are known to be inhibitors of the enzyme poly(ADP-ribose)polymerase, which is believed to be essential in the repair of irradiated cells after radiation. Such "potential lethal damage repair". (PLDR) is, of course, effected after the radiation treatment, typically over the course of several hours. While the net effect of inhibiting PLDR may be to enhance cell killing, the mechanism for thus enhancing the effect of the radiation treatment is different from that of radiosensitization. Agents which inhibit PLDR must be present during the repair period, and their presence during the irradiation itself is not required. On the other hand, radiosensitizers must be present during the radiation treatment, and can be removed immediately thereafter, without change in their effect.
Accordingly, it was surprising that some benzamide compounds, known only to inhibit poly(ADP-ribose)polymerase, exhibited a time dependence with respect to their effect on irradiated tumor cells which corresponds to that of the radiosensitizers.